Intranasal formulations

Drug formulation Pharmacokinetics and bioavailability of parental diazepam were compared with two novel intranasal diazepam formulations (intranasal solution and intranasal suspension) in a randomised, open-label, pilot study in 24 healthy volxmteers [9 ]. Participants received two intranasal and one intravenous dose of diazepam with 2 weeks washout period between doses. Both intranasal formulations were well tolerated. Diazepam concentration... 

The nasal tissue is highly vascularized and provides efficient systemic absorption. Compared with oral or subcutaneous administration, nasal administration enhances bioavailability and improves safety and efficacy. Chitosan enhances the absorption of proteins and peptide drugs across nasal and intestinal epithelia. Gogev et al. demonstrated that the soluble formulation of glycol chitosan has potential usefulness as an intranasal adjuvant for recombinant viral vector vaccines in cattle [276]. 

Besides the inhalative use, the development of a drug formulation for A9-THC has to address other bioavailabihty questions. A major problem is the hpophiUcity and poor solubiUty in water, hmiting oral uptake when given orally. Because of this, other parenteral routes of apphcation are imder investigation like puhnonal uptake by vaporization, subUngual or intranasal administration, and apphcation by injection of A9-THC incorporated in hpo-somes. 

The intranasal formulation is the preferred route of administration owing to ease of administration and fewer adverse effects, which mainly are local in nature. Adverse effects associated with the intranasal formulation include rhinitis, nasal irritation, and dryness. Hypersensitivity can develop with either formulation and should be considered before administering to patients with a suspected risk of hypersensitivity. 

Primary therapy is based on disease severity and type of hemorrhage.7 Most patients with mild to moderate disease and a minor bleeding episode can be treated with l-desamino-8-D-arginine vasopressin [desmopressin acetate (DDAVP)], a synthetic analog of the antidiuretic hormone vasopressin. DDAVP causes release of von Willebrand factor (vWF) and factor VIII from endogenous storage sites. This formulation increases plasma factor VIII levels by three- to fivefold within 30 minutes. The recommended dose is 0.3 mcg/kg intravenously (in 50 mL normal saline infused over 15 to 30 minutes) or subcutaneously or 300 meg intranasally via concentrated nasal spray every 12 hours. Peak effect with intranasal administration occurs 60 to 90 minutes after administration, which is somewhat later than with intravenous administration. Desmopressin infusion may be administered daily for up to 2 to 3 days. Tachyphylaxis, an attenuated response with repeated administration, may occur after several doses.8... 

Sumatriptan is available for oral, intranasal, and SC administration. The SC injection is packaged as an autoinjector device for self-administration by patients. When compared with the oral formulation, SC administration offers enhanced efficacy and a more rapid onset of action (10 vs. 30 minutes). Intranasal sumatriptan also has a faster onset of effect (15 minutes) than the oral formulation and produces similar rates of response. Approximately 30% to 40% of patients who respond to sumatriptan experience headache recurrence within 24 hours a second dose given at the time of recurrence is usually effective. However, routine administration of a second oral or SC dose does not improve initial efficacy rates or prevent subsequent recurrence. 

Olive, C., Schulze, K., Sun, H. K., Ebensen, T., Horvath, A., Toth, I., and Guzman, C. A. (2007). Enhanced protection against Streptococcus pyogenes infection by intranasal vaccination with a dual antigen component M protein/Sfbl lipid core peptide vaccine formulation. Vaccine 25, 1789-1797. 

In a more recent study, Webster et al. (2006) report the expression and characterization of lettuce-derived measles vaccine. The MV-H protein expressed in lettuce was demonstrated to be immunogenic in mice following intraperitoneal injection in the absence of adjuvant in addition to intranasal inoculation in the presence of a mucosal adjuvant. The highest response was observed in mice primed first with MV-H DNA and then boosted with an oral formulation of freeze-dried MV-H lettuce in conjunction with a mucosal adjuvant. In addition to this, the type of immune response was found to depend largely on the manner in which MV-H is presented to the immune system. Secreted and soluble forms of MV-H were demonstrated to induce a Th2 type response, while membrane-bound MV-H protein was found to be associated with a Thl response. 

Parenteral calcitonin (32 aa) formulations are used to regulate calcemia. Intranasal delivery of calcitonin, a potentially convenient alternative, produces low bioavailability and is not useful as such. Permeation enhancers, including mixed micelle formulations composed of either... 

STDHF has also been shown to enhance intranasal delivery of insulin. The bioavailability of insulin (51 aa) formulated as a nasal drop or spray containing STDHF was 16% to 47% in healthy volunteers [22].The... 

Ixe, W.A., B.A. Narog, T.W. Patapofl) and Y.J. Wang, Intranasal bioavailability of insulin powder formulations effect of permeation enhancer-to-protein ratio. J Pharm Sci, 1991. 80(8) 725-9. 

Leuprolide Agonist of GnRH receptors Increased LH and FSH secretion with intermittent administration reduced LH and FSH secretion with prolonged continuous administration Ovarian suppression, controlled ovarian hyperstimulation, central precocious puberty advanced prostate cancer Administered IV, SC, IM or intranasally depot formulations are available Toxicity Headache, lightheadedness, nausea, injection site reactions t symptoms of hypogonadism with continuous treatment... 

Ethylene glycols Formulation aid for nasal delivery Single and repeat-dose nasal toxicity (up to 14 days— intranasal rabbit) Mild local toxicity likely to be acceptable in clinical nasal formulations for short-term use 35... 

Hjortkjaer RK, Bechgaard E, Gizurason S, et al. Single- and repeated-dose local toxicity in the nasal cavity of rabbits after intranasal administration of different glycols for formulations containing benzodiazepines. J Pharm Pharmacol 1999 51(4) 377. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

Intranasal calcitonin is associated with fewer adverse effects than parenteral formulations, probably because of low systemic availability. However, a meta-analysis has confirmed that adverse events are poorly reported in clinical trials (21). The pooled relative risk for rhinitis from four trials (n = 1663) was 1.72, but this did not reach statistical significance. 

Agerholm, C., et al. 1994. Epithelial transport and bioavailability of intranasally administered human growth hormone formulated with the absorption enhancers didecanoyl-L-alpha-phospha-tidylcholine and alpha-cyclodextrins in rabbits. J Pharm Sci 83 1706. 

Additional factors influencing nasal peptide absorption include particle residence time and formulation pH and osmolarity. Ohwaki et al (10) measured the effect of solution pH and osmolarity on the intranasal absorption of secretin, a 27 amino acid peptide, in rats. Nasal secretin absorption, as measured by pancreatic secretion rates, was maximal at a formulation pH of 3.0 almost eight times greater than at neutral pH. Solution osmolarity had less effect overall on secretin absorption, maximal absorption occurring in a hyperosmolar saline solution of 0.462 M. 

These concerns largely preclude the utility of thermoplastic polymers as the primary choice of container closure system for protein and peptide therapeutics, although the formulation scientist should be aware of the potential advantages of these systems, such as the ease of manufacturability and their cost. These systems are also finding greater utility in intranasal and pulmonary delivery systems. 

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